title: Alterations in deoxyribonucleic acid (DNA) methylation patterns of Calca, Timp3, Mmp2, and Igf2r are associated with chronic cystitis in a cyclophosphamide-induced mouse model.
abstract: OBJECTIVE
  To determine whether epigenetic changes occur during cyclophosphamide-induced chronic bladder inflammation in mice.
  
  
  METHODS
  Epigenetic changes play a role in the regulation of inflammatory genes in noncancer diseases such as asthma and chronic obstructive pulmonary disease. However, epigenetic (deoxyribonucleic acid [DNA] methylation) changes during chronic bladder inflammation have not been previously described. Chronic cystitis was induced in 3 groups of adult CD-1 male mice using multiple weight-based intraperitoneal cyclophosphamide injections during a 3-month period. Histopathologic and MethyLight assays were performed on specimens with chronic bladder inflammation at multiple points to monitor cystitis progression and DNA methylation changes compared with the control specimens.
  
  
  RESULTS
  Histopathologic analysis showed the most extensive edema and urothelial sloughing at the 1-month point. MethyLight analyses revealed statistically significant changes in DNA methylation associated with the Calca, Timp3, Mmp2, and Igf2r genes in the chronic bladder injury model. The changes in DNA methylation associated with chronic cystitis were DNA hypomethylation of the Calca gene in the control tissue and DNA hypermethylation for the Calca, Timp3, Mmp2, and Igf2r genes compared with that in the control tissue.
  
  
  CONCLUSIONS
  DNA methylation changes were noted in the Calca, Timp3, Mmp2, and Igf2r genes during chronic cystitis in a murine model. Epigenetic changes appear to play a role in the regulation of inflammatory bladder genes during chronic cystitis; however, additional studies are needed to elucidate the pathways associated with these genes.
authors.affiliation: Division of Pediatric Urology, Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: In-Seon
authors.initials: IS
authors.lastname: Choi
authors.forename: Kevin
authors.initials: K
authors.lastname: Yu
authors.forename: Jayoung
authors.initials: J
authors.lastname: Kim
authors.forename: Erika
authors.initials: E
authors.lastname: De Guzman
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.forename: Shirley
authors.initials: S
authors.lastname: Oghamian
authors.forename: Hee Ju
authors.initials: HJ
authors.lastname: Kim
authors.forename: Kyung Hwa
authors.initials: KH
authors.lastname: Lee
authors.forename: Cindy
authors.initials: C
authors.lastname: Carroll
authors.forename: Binh N
authors.initials: BN
authors.lastname: Trinh
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.forename: Sahar
authors.initials: S
authors.lastname: Houshdaran
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.forename: Gangning
authors.initials: G
authors.lastname: Liang
authors.forename: Chester J
authors.initials: CJ
authors.lastname: Koh
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000235:genetics*; D015740:Calcitonin Gene-Related Peptide; D002908:Chronic Disease; D018899:CpG Islands; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D051379:Mice; D011498:Protein Precursors / Q000235:genetics*; D017527:Receptor, IGF Type 2 / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*
chemical_list: C000606590:Calca protein, mouse; D011498:Protein Precursors; D017527:Receptor, IGF Type 2; D019717:Tissue Inhibitor of Metalloproteinase-3; D003520:Cyclophosphamide; D002116:Calcitonin; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D015740:Calcitonin Gene-Related Peptide